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PubMed2005

Mutually exclusive subsets of BH3-only proteins are activated by the p53 and c-Jun N-terminal kinase/c-Jun signaling pathways during cortical neuron apoptosis induced by arsenite.

The c-Jun N-terminal protein kinase (JNK)/c-Jun and p53 pathways form distinct death-signaling modules in neurons that culminate in Bax-dependent apoptosis. To investigate whether this signaling autonomy is due to recruitment of particular BH3-only proteins, we searched for a toxic signal that would activate both pathways in the same set of neurons. We show that arsenite activates both the JNK/c-Jun and p53 pathways in cortical neurons, which together account for >95% of apoptosis, as determined by using the mixed-lineage kinase (JNK/c-Jun) pathway inhibitor CEP11004 and p53-null mice. Despite the coexistence of both pathways in at least 30% of the population, Bim mRNA and protein expression was increased only by the JNK/c-Jun signaling pathway, whereas Noxa and Puma mRNA and Puma protein expression was entirely JNK/c-Jun independent. About 50% of Puma/Noxa expression was p53 dependent, with the remaining signal being independent of both pathways and possibly facilitated by arsenite-induced reduction in P-Akt. However, functionally, Puma was predominant in mediating Bax-dependent apoptosis, as evidenced by the fact that more than 90% of apoptosis was prevented in Puma-null neurons, although Bim was still upregulated, while Bim- and Noxa-null neurons died similarly to wild-type neurons. Thus, the p53 and JNK/c-Jun pathways can activate mutually exclusive subclasses of BH3-only proteins in the same set of neurons. However, other factors besides expression may determine which BH3-only proteins mediate apoptosis.

Animals↗
PubMed1996

Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas.

Glioblastoma multiforme, the most malignant human brain tumor, may develop de novo (primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). We present further evidence that primary and secondary glioblastomas constitute distinct disease entities which develop through the acquisition of different genetic alterations. We analyzed p53 mutations, p53 protein accumulation and epidermal growth factor receptor (EGFR) overexpression in 49 biopsies classified as primary or secondary glioblastoma according to clinical and histopathologic criteria. Patients with primary glioblastoma were selected on the basis of a clinical history of less than 3 months and histopathologic features of glioblastoma at the first biopsy (19 cases; mean age, 55 years). The diagnosis of secondary glioblastomas required at least two biopsies and clinical as well as histologic evidence of progression from low grade or anaplastic astrocytoma (30 cases; mean age, 39 years). DNA sequence analysis showed that p53 mutations were rare in primary glioblastomas (11%) while secondary glioblastomas had a high incidence of p53 mutations (67%), of which 90% were already present in the first biopsy. The incidence of p53 protein accumulation (nuclear immunoreactivity to PAb 1801) was also lower in primary (37%) than in secondary glioblastomas (97%). In contrast, immunoreactivity for the EGF receptor prevailed in primary glioblastomas (63%) but was rare in secondary glioblastomas (10%). Only one out of 49 glioblastomas showed EGFR overexpression and a p53 mutation. These data indicate that overexpression of the EGF receptor and mutations of the p53 tumor suppressor gene are mutually exclusive events defining two different genetic pathways in the evolution of glioblastoma as the common phenotypic endpoint.

Adult↗
PubMed1989

Mutually exclusive synthetic pathways for sea urchin mitochondrial rRNA and mRNA.

The structure and abundance of mitochondrial transcripts in sea urchin embryos were investigated by a combination of RNA blot-hybridization, S1 mapping, and primer extension assays. Between the egg and blastula stages, the relative abundance of mitochondrial rRNAs declined slightly, while that of mitochondrial mRNAs increased up to 10-fold. Fine mapping of the termini of the rRNAs and of the adjacent transcripts indicated that, although they appeared to be butt-joined at their 5' ends to the upstream transcripts, tRNA-Phe 5' to the small subunit (12S) rRNA and NADH dehydrogenase subunit 2 mRNA 5' to the large subunit (16S) rRNA, respectively, their 3' ends were found to overlap the 5' ends of the downstream transcripts. 12S rRNA was found to extend 7 to 13 nucleotides into the sequence of tRNA-Glu; 16S rRNA was shown to terminate 3 to 5 nucleotides inside the coding region of cytochrome oxidase subunit 1 (COI) and 8 to 10 nucleotides from the mapped 5' end of COI mRNA. The rRNAs and the downstream transcripts must therefore be synthesized by distinct pathways, either by alternative processing of the same primary transcript(s) or by processing of different precursors. In either case, the events which select the ribosomal 3' ends preclude the production of functional transcripts of the downstream genes from the same precursor molecule. No developmental alterations in transcript structure were detected. We propose that mitochondrial RNA levels are regulated in early development by the selection of alternate and mutually exclusive RNA-processing pathways.

Animals↗
PubMed1993

Mutually exclusive binding of two cellular factors within a critical promoter region of the gene for the IE110k protein of herpes simplex virus.

We have examined the cis- and trans-acting factors involved in constitutive transcription of the promoter for the IE110k protein of herpes simplex virus type 1. Our results indicate that while the IE110k gene is activated by Vmw65, it also exhibits very efficient constitutive expression approximating that from the simian virus 40 early enhancer-promoter region. We show that despite the presence of multiple copies of the octamer consensus site which mediate Oct-1 binding and subsequent Vmw65 activation, these upstream sequences have a minor effect on constitutive transcription. By progressive exonuclease digestion and subsequent site-directed mutagenesis of the promoter, we have identified a 15-bp region (termed the EC region), from position -89 to -74, which is required for efficient constitutive expression from the IE110k promoter. We demonstrate that two cellular proteins interact with this region and, by competition and methylation interference analyses, show they have distinct but overlapping sequence requirements for binding. One of these proteins is identified as NF-Y, a CCAAT box-binding factor, which binds an inverted CCAAT box located between positions -71 and -75. The second cellular factor, F2, appears to be novel and binds a region with the sequence CGCGCGGC CAT which overlaps the 3' end of the CCAAT box. The terminal AT of the recognition site for F2 represents, on the opposite strand, the terminal AT of the CCAAT box, and these and adjacent bases are critically required for the binding of both factors. These results together with further competition analysis indicate that these factors bind in a mutually exclusive manner to the EC region. The implications of these results for regulation of expression of the IE110k gene are discussed.

Animals↗
PubMed1996

Butylated hydroxytoluene and inorganic phosphate plus Ca2+ increase mitochondrial permeability via mutually exclusive mechanisms.

Mitochondria undergo a permeability transition (PT)2, i.e., become nonselectively permeable to small solutes, in response to a wide range of conditions/compounds. In general, opening of the permeability transition pore (PTP) is Ca2+- and P(i)-dependent and is blocked by cyclosporin A (CsA), trifluoperazine (TFP), ADP, and butylated hydroxytoluene (BHT). Gudz and coworkers have reported [7th European Bioenergetics Conference, EBEC Short Reports (1992) 7, 125], however, that, under some conditions, BHT increases mitochondrial permeability via a process that may not share all of these characteristics. Specifically, they determined that the BHT-induced permeability transition was independent of Ca2+ and was insensitive to CsA. We have used mitochondrial swelling to compare in greater detail the changes in permeability induced by BHT and by Ca2+ plus P(i) with the following results. (1) The dependence of permeability on BHT concentration is triphasic: there is a threshold BHT concentration (ca. 60 nmol BHT/ mg mitochondrial protein) below which no increase occurs; BHT enhances permeability in an intermediate concentration range; and at high BHT concentrations (>120 nmol/mg) permeability is again reduced. (2) The effects of BHT depend on the ratio of BHT to mitochondrial protein. (3) Concentrations of BHT too low to induce swelling block the PT induced by Ca2+ and P(i). (4) The dependence of the Ca2+-triggered PT on P(i) concentration is biphasic. Below a threshold of 50-100 mu M, no swelling occurs. Above this threshold swelling increases rapidly. (5) P(i) levels too low to support the Ca2+-induced PT inhibit BHT-induced swelling. (6) Swelling induced by BHT can be stimulated by agents and treatments that block the PT induced by Ca2+ plus P(i). These data suggest that BHT and Ca2+ plus P(i) increase mitochondrial permeability via two mutually exclusive mechanisms.

Animals↗
PubMed1994

4-Aminopyridine binding and slow inactivation are mutually exclusive in rat Kv1.1 and Shaker potassium channels.

In the present study we have used two-electrode voltage-clamping of Xenopus oocytes expressing either Kv1.1 or Shaker B (ShB) delta 6-46 K+ channels to examine the effects of 4-aminopyridine (4-AP) on the process of slow inactivation. Neither of these channels exhibits fast inactivation. Channel activation was required for block by 4-AP in both channel types. In the absence of drug, inactivation of Kv1.1 and ShB delta 6-46 channels at 0 mV was biexponential [tau fast = 7.8 +/- 0.3 sec, tau slow = 33.9 +/- 0.9 sec, and Aslow/(Afast + Aslow) = 0.79 +/- 0.02 (n = 10) for Kv1.1 and tau fast = 3.5 +/- 0.4 sec, tau slow = 13.1 +/- 1.8 sec, and Aslow/(Afast + Aslow) = 0.35 +/- 0.06 (n = 3) for ShB delta 6-46]. In the presence of 4-AP, the rates of inactivation of Kv1.1 and ShB delta 6-46 were markedly slowed, resulting in a crossover phenomenon where, in the presence of drug, the outward current was smaller than control at the beginning of the depolarizing pulse but crossed over during the pulse to become larger than the control. The most obvious change induced by 0.2 mM 4-AP was a 2-fold slowing of the slow phase of inactivation [tau fast = 3.9 +/- 1.1 sec, tau slow = 67.1 +/- 3.6 sec, and Aslow/(Afast + Aslow) = 0.85 +/- 0.04 (n = 4) for Kv1.1 and tau fast = 3.5 +/- 0.4 sec, tau slow = 23.7 +/- 2.6 sec, and Aslow/(Afast + Aslow) = 0.75 +/- 0.02 (n = 3) for ShB delta 6-46, in the presence of 0.2 mM 4-AP]. In addition, there was a significant increase in the contribution of the slower phase of inactivation of ShB delta 6-46 channels in the presence of 4-AP. The slowed inactivation in the presence of 4-AP was accompanied by removal of 4-AP block. These results are consistent with the processes of 4-AP block and slow inactivation of Kv1.1 and ShB delta 6-46 channels being mutually exclusive.

4-Aminopyridine↗
PubMed2003

Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events.

The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three groups in terms of proliferation rate or expression of anti-apoptotic proteins. However, cyclin D1+ cases were always well differentiated and were more likely to show a lymphoplasmocytoid differentiation (chi-square = 9.55). Overall, constitutive activation of Stat 3 was found in almost half (48%) of the investigated MM cases. However, this does not seem to have a major impact on the expression of anti-apoptotic proteins and proliferation. We showed that cyclin D1 overexpression and Stat 3 activation are, mutually exclusive events in MM (P = 0.0066). The universal expression of Mcl-1, independent of activated Stat 3, suggests that its expression is constitutive and that it might play an important role in the pathogenesis of MM.

Aged↗
PubMed1999

Posttraumatic stress disorder and traumatic brain injury: are they mutually exclusive?

It has been suggested that posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) must be mutually incompatible disorders. However, growing empirical evidence has begun to question this. Evidence suggests that although PTSD may be relatively rare among the TBI population, some TBI patients seem to develop PTSD. We suggest two theoretical routes through which PTSD might develop in TBI patients: through nonconscious processes in individuals who are subsequently amnesic, but who were conscious at the time of the traumatic episode and through subsequent appraisal processes in individuals who were unconscious during the traumatic episode.

Adaptation, Psychological↗
PubMed1989

Mutual exclusion occurs in a Chlorella-like green alga inoculated with two viruses.

Progeny viruses resulting from dual inoculations with different and near-isogenic viruses of a Chlorella-like green alga were distinguished by immunoblotting. Plaques arising from single cells inoculated with two viruses usually contained only one of the viruses. Thus the viruses mutually exclude one another. In some combinations the ratio of viruses (as infective centres) recovered differed significantly from the input ratio.

Adhesiveness↗
PubMed1996

Complementary and mutually exclusive activities of decapentaplegic and wingless organize axial patterning during Drosophila leg development.

Growth and patterning of the Drosophila leg are organized by three secreted proteins: Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Hh is secreted by posterior cells; it acts at short range to induce dorsal anterior cells to secrete Dpp and ventral anterior cells to secrete Wg. Here we show that the complementary patterns of dpp and wg expression are maintained by mutual repression: Dpp signaling blocks wg transcription, whereas Wg signaling attenuates dpp transcription. We also show that this mutual repression is essential for normal axial patterning because it ensures that the dorsalizing and ventralizing activities of Dpp and Wg are restricted to opposite sides of the leg primordium and meet only at the center of the primordium to distalize the appendage.

Animals↗
PubMed1996

Mutually exclusive distribution of the focal adhesion associated proteins and the erythrocyte membrane skeleton proteins in the human fibroblast plasma membrane undercoat.

The ends of stress fibers in the basal portion of cells (basal stress fibers) are anchored to focal adhesions, and stress fibers in the apical part of cells (apical stress fibers) are attached to the apical membrane, forming a structure (the apical plaque; KATOH, K. et al. (1995). Cell Motil. Cytoskel., 31: 177-195) resembling the focal adhesion. In addition to these two sites, stress fibers also make lateral contact with the plasma membrane but little is known about the molecular composition of this type of stress fiber-membrane interaction sites. Several actin-membrane association types are known, each employing a different set of proteins, and the focal adhesion and the erythrocyte membrane skeleton are the best characterized systems. We investigated by immunofluorescence microscopy if there is any morphological basis for the involvement of the erythrocyte membrane proteins in the stress fiber-plasma membrane association sites in cultured human fibroblasts. Our results indicated that fodrin (nonerythrocyte type spectrin) and ankyrin were generally associated with the plasma membrane, but that they were clearly excluded from the focal adhesion, the apical plaque and the stress fiber. Thus, it appears that the spectrin and the integrin based actin-membrane association systems are mutually excluded in the fibroblast membrane undercoat. Protein localization at the lateral stress fiber-membrane association site was also studied. Our data indicated that, while talin, vinculin, paxillin, fibronectin receptor and integrin beta 1 were present at the three stress fiber-membrane association sites, vitronectin receptor and integrin alpha v were absent from the apical plaque and the lateral association site. While the plasma membrane at the focal adhesion adheres tightly to a solid substrate, the cell surface of the apical plaque is free. Although the lateral association site faces the substrate, the molecular composition of this site is similar to that of the apical plaque.

Actin Cytoskeleton↗
PubMed1993

Development of functional diversity in mouse macrophages. Mutual exclusion of two phenotypic states.

The objective of this study was to investigate the mechanisms that contribute to the generation of macrophage functional diversity. Exposure of mouse bone marrow-derived macrophages to beta-1,3-glucan, a particulate inflammatory stimulus, or polyinosinate-polycytidylate (poly[I:C]), a stimulus of macrophage cytocidal activation, induced distinct and stimulus-specific patterns of gene expression. These changes were characterized by an up-regulation of the expression of the acid hydrolase beta-glucuronidase and platelet-derived growth factor B following incubation with beta-1,3-glucan and a stimulation of the expression of the complement component Bf, beta-interferon, and the reactive nitrogen intermediates NO2/NO3 during incubation with poly[I:C]. The induction of Bf expression by poly[I:C] could not be explained on the basis of distinct subpopulations of cells since in situ hybridization with a mouse Bf cRNA probe revealed a uniform and substantial increase in Bf expression by the entire population of cells. Incubation of macrophages with beta-1,3-glucan before stimulation with poly[I:C] was found to strongly attenuate the expression of Bf and beta-interferon. Conversely, incubation with poly[I:C] prior to exposure to beta-1,3-glucan substantially blocked the stimulation of beta-glucuronidase and platelet-derived growth factor B expression, indicating that these two responses were expressed in a mutually antagonistic fashion. However, after removal of either stimulus and following a period in which the primary response was allowed to decay, the cells regained their capacity to subsequently respond to either the same stimulus or to a different stimulus. Collectively, these findings indicate, first, that the heterogeneity of gene expression seen in response to poly[I:C] represents an adaptive response of the entire macrophage population rather than the restricted responses of distinct subpopulations of cells. Second, macrophages respond to these stimuli in a sequential fashion. These findings thus have a significant bearing on our understanding of the regulation of macrophage heterogeneity in host defense.

Animals↗
PubMed1988

Intraneuronal and extracellular neurofibrillary tangles exhibit mutually exclusive cytoskeletal antigens.

We examined the possibility that neurofibrillary tangles (NFTs) were heterogeneous in postmortem hippocampus from 22 patients with or without senile dementia of the Alzheimer type. Intraneuronal NFTs and extracellular, or "ghost," NFTs were recognized in situ by only one or the other of two monoclonal antibodies. The first monoclonal antibody, RMO87, stained only intraneuronal NFTs and is specific for phosphate-dependent epitopes in tau and the two high molecular weight neurofilament proteins. The second monoclonal antibody, 2.2B10, is specific for glial fibrillary acidic protein, and it stained only the RMO87-negative extracellular NFTs. Treatment of sections with alkaline phosphatase or sodium dodecyl sulfate, and the isolation of NFTs from hippocampus, did not expose RMO87 binding sites in extracellular NFTs. These observations indicate that neurofilament-like and tau-like epitopes can be lost from NFTs in situ, and that at least two populations of morphologically and immunochemically distinct NFTs exist.

Aged↗
PubMed2003

Determining the optimal combinations of mutually exclusive interventions: a response to Hutubessy and colleagues.

Hutubessy and colleagues have suggested a technique for decision-makers to employ in determining the optimal combination of interventions. This technique requires the adoption of Monte Carlo simulation analysis to identify the probability that a certain program will be included in an optimal mix given the uncertainty around the program's expected costs and benefits. In this response, it will be demonstrated that this methodology can lead to potential inefficiencies arising through the dependence of such probabilities on decisions relating to other programs and the failure to consider the opportunity costs of obtaining increased health benefits. A simple alternative approach is suggested which avoids these problems.

Budgets↗
PubMed2001

Mutually exclusive apicobasolateral sorting of two oligodendroglial membrane proteins, proteolipid protein and myelin/oligodendrocyte glycoprotein, in Madin-Darby canine kidney cells.

Oligodendrocytes elaborate an extensive membrane network that ensheathes CNS axons in multilamellar wrappings. A compaction process excludes much of the cytoplasm in mature myelin membranes, giving rise to distinct lipid/protein compositions in two membrane compartments (compact myelin and membranes of the cell body and processes). Insofar as oligodendrocytes arise from neuroepithelial progenitors, it seems likely that some elements are shared for protein targeting by these two cell types. We hypothesized that certain membrane proteins targeting different oligodendroglial membrane compartments would preferentially sort to opposite domains when transfected into Madin-Darby canine kidney (MDCK) epithelial cells. Myelin/oligodendrocyte glycoprotein (MOG) is found in uncompacted membrane (cell body, processes), and it sorts exclusively to MDCK basolateral membrane. Proteolipid protein (PLP) is found in compact myelin, and it sorts exclusively to MDCK apical membrane. Myelin-associated glycoprotein (MAG) is primarily in the periaxonal inner loop of myelin; however, it fails to target preferentially within MDCK cells. This inability of MAG to sort within MDCK cells suggests a lack of required oligodendroglial-specific targeting components. In contrast, the sorting machinery in both oligodendrocytes and MDCK cells recognizes targeting signals for MOG and PLP, and we propose that these oligodendroglial membrane proteins delineate cognate basolateral and apical domains, respectively.

Animals↗
PubMed2001

Mutual exclusion of apoptosis and hsp70 in human vein intimal hyperplasia in vitro.

BACKGROUND: Apoptosis of vascular smooth muscle cells (VSMC) plays a role in physiological vascular remodeling, as well as in disease states such as atherosclerosis and restenosis after angioplasty. Heat shock protein 70 (hsp70) may protect the cell against apoptosis and/or necrosis. In this study, we examined hsp70 expression and its temporal relationship to cell survival or death in a model of intimal vein hyperplasia in vitro. METHODS: Segments of human saphenous veins were placed into culture. At different days vein segments were serum-starved or exposed to heat shock. Apoptosis and hsp70 expression were analyzed by Western blot, immunohistochemistry, and TUNEL assay. RESULTS: A marked intimal vein hyperplasia developed after 14 days of culture when compared with baseline. hsp70 was present at baseline and disappeared during culture. Heating during culture could not up-regulate hsp70. The apoptotic markers were absent at baseline and present during normal culture. Conversely, serum starvation stimulated strong hsp70 expression coincidental with the disappearance of apoptotic markers. CONCLUSIONS: Stimulation of veins during culture with serum resulted in hyperplasia, apoptosis, and inhibition of hsp70 expression. Down-regulation of hsp70 may permit apoptosis and vessel wall remodeling in this model.

Apoptosis↗
PubMed1988

Acquired immune deficiency syndrome (AIDS) and autoimmunity--mutually exclusive entities?

Loss of normal immune homeostasis occurs in acquired immune deficiency syndrome (AIDS). We evaluated patients at the University of Cincinnati and New York University Medical Centers for serologic evidence of autoimmune changes. Specifically, tests for antinuclear and organ-specific antibodies by immunofluorescence, antisperm and anti-seminal plasma antibodies, rheumatoid factor by latex and sensitized sheep cell agglutination techniques, anti-polyadenosine (poly A), and single-stranded DNA antibodies were performed in human immunodeficiency virus (HIV) antibody-positive sera. A parallel study of mitogen responsiveness was performed and showed inhibition of response by AIDS and AIDS-related complex (ARC) sera. In spite of evidence of polyclonal B-cell activation, hyperglobulinemia, and the presence of antibodies to many infectious agents, as well as the known cellular immune abnormalities, the patients tested had a striking absence of these autoantibodies. The only major difference noted from normal controls, was a low but significant level of antibody binding to poly A. The autoimmune connective tissue diseases were not observed in this group of patients.

Acquired Immunodeficiency Syndrome↗